A New Synthesis of 3-Arylideneamino-and 3-Alkylideneamino-Substituted Hydantoins

: A novel straightforward approach to 3-arylideneamino-and 3-alkylideneamino-hydantoins has been developed. It is based on reaction of readily available 4-(tosylmethyl)semicarbazones with NaCN in DMF followed by heating of the obtained α -(4-semicarbazono)nitriles with conc. HCl.


Scheme 1. Straightforward approach to N-alkylidene-and N-arylidene-3-aminohydantoins 3.
Recently, we have shown that N-(tosylmethyl)-substituted ureas smoothly react with sodium cyanide in aprotic solvents to give the corresponding nitriles of α-ureidocarboxylic acids [38]. However, in the case of 4-(tosylmethyl)semicarbazones, the outcome of the cyanation is not obvious due to significant structural differences between ureido and semicarbazono groups.

Results and Discussion
First, we studied the reaction of 4-(tosylmethyl)semicarbazone 1a with NaCN under different conditions with varying reagents ratio, solvent, temperature, and reaction time. We found that, in general, this reaction resulted in the expected nitrile 2a (Scheme 2).
However, in contrast to the reaction of N-(tosylmethyl)ureas with NaCN [38], the outcome of the reaction of sulfone 1a with NaCN is extremely sensitive to reaction conditions (Table 1). Using DMF as a solvent, an increase in temperature (entry 1 vs. entry 2), reaction time (entry 3 vs. entry 4), and excess of NaCN (entry 2 vs. entry 3) lead to a significant increase in the number and amount of side products. Presumably, these side products arise from further transformations of the initially formed nitrile 2a under the reaction conditions. One of such transformations involves base-catalyzed cyclization of 2a into imine 5a or enamine 4a. Indeed, the reaction of sulfone 1a with NaCN (1.1 equiv.) in DMF (0 °C, 2.75 h) gave a mixture of nitrile 2a along with a side product (Table 1, entry 2). 1 H NMR spectrum of the latter in DMSO-d6 showed three singlet signals at 10.26, 9.81, and 5.01 ppm with relative intensities of 1:1:2, which can be assigned respectively to the NH, CH=N, and NH2 protons in enamine 4a. The structure of this compound was also confirmed by its 13 C NMR spectrum and DFT computational data (see below). Thus, this synthesis afforded a mixture of 2a and 4a in a ratio of 85:15.
A significantly higher ability of nitrile 2a to cyclize under basic conditions compared with nitriles of α-ureidocarboxylic acids [38] can be explained by increased NH acidity of semicarbazones. Deprotonation of the N(2)H in 2a with NaCN gives the corresponding conjugated base followed by its cyclization into imine 5a which tautomerizes into enamine 4a.
We studied the behavior of nitrile 2a towards various bases (NaCN, DBU, KOH, K2CO3, NEt3) at room temperature. In all cases, a rapid conversion of 2a into enamine 4a and various other compounds was observed. For example, the treatment of 2a with 0.05 equivalents of KOH in EtOH (rt, 2 h 23 min) followed by precipitation of the product with ice water afforded 4a in 84% yield and about 70% purity ( 1 H NMR data). The 13 C NMR spectrum of 4a in DMSO-d6 showed the presence of signals at 149.8, 148.4, and 96.8 ppm corresponding to the CH=N, C(2), and C(5) carbon, respectively. These chemical shifts are consistent with those calculated for the most stable conformer of tautomeric structure 4a (148.3, 152.8, and 88.9 ppm, respectively) by the GIAO method at the WC04/6-311+G(2d,p) level of theory using the DFT B3LYP/6-311++G(d,p) optimized geometries (DMSO solution, the PCM solvation model) and significantly differ from those calculated for the most stable stereoisomer of tautomeric structure 5a (149.1, 158.1, and 53.6 ppm, respectively). The DFT calculation also demonstrated that the most stable stereoisomers of 5a and 4a are quite close in stability in DMSO solution (ΔE = 0.09 kcal/mol and ΔG = 0.72 kcal/mol in favor of 5a with (Z)configuration of the C=N double bond). Thus, it can be assumed that these stereoisomers are in dynamic equilibrium in DMSO. Apparently, some deviation of the calculated and experimental chemical shifts in the 13 C-NMR spectrum of compound 4a (see above) can be explained by this equilibrium.
Under the optimized conditions, the reaction of 1a with 1.05 equivalents of NaCN (DMF, 0 °C, 1 h) followed by precipitation of the product with ice water afforded cyanide 2a in 98% yield and excellent purity (Table 1, entry 4). The use of other solvents (MeCN, MeOH, EtOH) in the reaction of sulfone 1a with NaCN resulted in quite unsatisfactory purity of 2a (entries [6][7][8]. These optimal conditions were next applied to the reaction of sulfones 1b-f with NaCN providing the expected nitriles 2b-f in yields of 86-93% and high levels of purity (Scheme 3, Table 2). Scheme 3. Synthesis of nitriles of α-(4-semicarbazido)carboxylic acids 2a-f. Next, we studied acid-catalyzed hydrolysis of nitriles of α-(4-semicarbazido)carboxylic acids 2af. Previously, we demonstrated that treatment of α-ureidonitriles with conc. HCl at room temperature gives the corresponding amides in high yields [38]. In contrast, the reaction of nitrile 2a with conc. HCl at room temperature for 24 h afforded hydantoin 3a as the main compound (Scheme 4) together with various side products (about 40%, 1 H NMR data), among which enamine 4a was observed (3a/4a = 87:13). Similar results were obtained when nitrile 2b was reacted with conc. HCl at room temperature.
Treatment of nitrile 2a with conc. HCl at 39 °C for 7 h or 20 h did not improve the hydrolysis efficiency. Only when heating of 2a in conc. HCl (boiling water bath, 40 min) was used, spectroscopically pure hydantoin 3a was obtained in 82% yield. Under similar conditions, hydantoins 3b-e were prepared from nitriles 2b-e in 51-85% yields. In the case of nitrile 2f, the hydrolysis was not so straightforward, and hydantoin 3f was isolated only in a 14% yield.

Conclusions
In summary, a novel straightforward approach to N-alkylidene-and N-arylidene-3aminohydantoins has been developed. This approach is based on reaction of readily available 4-(tosylmethyl)semicarbazones with sodium cyanide in DMF (0 °C, 1 h) followed by treatment of the obtained nitriles of α-(4-semicarbazono)carboxylic acids with conc. HCl (boiling water bath, 40 min).